A physiologic rise in cytoplasmic calcium ion signal increases pannexin1 channel activity via a C-terminus phosphorylation by CaMKII.

Pannexin1 (Panx1) channels are ubiquitously expressed in vertebrate cells and are widely accepted as adenosine triphosphate (ATP)-releasing membrane channels. Activation of Panx1 has been associated with phosphorylation in a specific tyrosine residue or cleavage of its C-terminal domains. In the present work, we identified a residue (S394) as a putative phosphorylation site by Ca2+/calmodulin-dependent kinase II (CaMKII). In HeLa cells transfected with rat Panx1 (rPanx1), membrane stretch (MS)-induced activation-measured by changes in DAPI uptake rate-was drastically reduced by either knockdown of Piezo1 or pharmacological inhibition of calmodulin or CaMKII. By site-directed mutagenesis we generated rPanx1S394A-EGFP (enhanced green fluorescent protein), which lost its sensitivity to MS, and rPanx1S394D-EGFP, mimicking phosphorylation, which shows high DAPI uptake rate without MS stimulation or cleavage of the C terminus. Using whole-cell patch-clamp and outside-out excised patch configurations, we found that rPanx1-EGFP and rPanx1S394D-EGFP channels showed current at all voltages between ±100 mV, similar single channel currents with outward rectification, and unitary conductance (∼30 to 70 pS). However, using cell-attached configuration we found that rPanx1S394D-EGFP channels show increased spontaneous unitary events independent of MS stimulation. In silico studies revealed that phosphorylation of S394 caused conformational changes in the selectivity filter and increased the average volume of lateral tunnels, allowing ATP to be released via these conduits and DAPI uptake directly from the channel mouth to the cytoplasmic space. These results could explain one possible mechanism for activation of rPanx1 upon increase in cytoplasmic Ca2+ signal elicited by diverse physiological conditions in which the C-terminal domain is not cleaved.

Seroprevalence and risk factors associated with hepatitis C: a cross-sectional study of persons who inject drugs in Puerto Rico, 2018.

BACKGROUND: People Who Inject Drugs (PWID) are at a higher risk of acquiring bloodborne infections. We aimed to estimate the seroprevalence of the Hepatitis C Virus (HCV) in PWID and identify correlates and risk factors using data from the Puerto Rico National HIV Behavioral Surveillance System, PWID cycle 5, conducted in 2018. METHODS: A total of 502 San Juan Metropolitan Statistical Area participants were recruited through the Respondent Driven Sampling method. Sociodemographic, health-related, and behavioral characteristics were assessed. Testing for HCV antibodies was completed after the face-to-face survey. Descriptive and logistic regression analyses were performed. RESULTS: Overall seroprevalence of HCV was 76.5% (95% CI: 70.8-81.4%). A significantly (p < 0.05) higher HCV seroprevalence was observed among PWID with the following characteristics: heterosexuals (78.5%), high school graduates (81.3%), tested for sexually transmitted infections (STI) in the past 12 months (86.1%), frequent speedball injection (79.4%), and knowing the HCV serostatus of the last sharing partner (95.4%). Adjusted logistic regression models showed that having completed high school and reported STI testing in the past 12 months were significantly associated with HCV infection (ORa = 2.23; 95% CI: 1.06-4.69; ORa = 2.14; 95% CI: 1.06-4.30, respectively). CONCLUSIONS: We report a high seroprevalence of HCV infection in PWID. Social health disparities and potential missed opportunities validate the continuing call for local action for public health and prevention strategies.

TNF-α Plus IL-1ß Induces Opposite Regulation of Cx43 Hemichannels and Gap Junctions in Mesangial Cells through a RhoA/ROCK-Dependent Pathway.

Connexin 43 (Cx43) is expressed in kidney tissue where it forms hemichannels and gap junction channels. However, the possible functional relationship between these membrane channels and their role in damaged renal cells remains unknown. Here, analysis of ethidium uptake and thiobarbituric acid reactive species revealed that treatment with TNF-α plus IL-1ß increases Cx43 hemichannel activity and oxidative stress in MES-13 cells (a cell line derived from mesangial cells), and in primary mesangial cells. The latter was also accompanied by a reduction in gap junctional communication, whereas Western blotting assays showed a progressive increase in phosphorylated MYPT (a target of RhoA/ROCK) and Cx43 upon TNF-α/IL-1ß treatment. Additionally, inhibition of RhoA/ROCK strongly antagonized the TNF-α/IL-1ß-induced activation of Cx43 hemichannels and reduction in gap junctional coupling. We propose that activation of Cx43 hemichannels and inhibition of cell-cell coupling during pro-inflammatory conditions could contribute to oxidative stress and damage of mesangial cells via the RhoA/ROCK pathway.

The FGF2-induced tanycyte proliferation involves a connexin 43 hemichannel/purinergic-dependent pathway.

In the adult hypothalamus, the neuronal precursor role is attributed to the radial glia-like cells that line the third-ventricle (3V) wall called tanycytes. Under nutritional cues, including hypercaloric diets, tanycytes proliferate and differentiate into mature neurons that moderate body weight, suggesting that hypothalamic neurogenesis is an adaptive mechanism in response to metabolic changes. Previous studies have shown that the tanycyte glucosensing mechanism depends on connexin-43 hemichannels (Cx43 HCs), purine release, and increased intracellular free calcium ion concentration [(Ca2+ )i ] mediated by purinergic P2Y receptors. Since, Fibroblast Growth Factor 2 (FGF2) causes similar purinergic events in other cell types, we hypothesize that this pathway can be also activated by FGF2 in tanycytes to promote their proliferation. Here, we used bromodeoxyuridine (BrdU) incorporation to evaluate if FGF2-induced tanycyte cell division is sensitive to Cx43 HC inhibition in vitro and in vivo. Immunocytochemical analyses showed that cultured tanycytes maintain the expression of in situ markers. After FGF2 exposure, tanycytic Cx43 HCs opened, enabling release of ATP to the extracellular milieu. Moreover, application of external ATP was enough to induce their cell division, which could be suppressed by Cx43 HC or P2Y1-receptor inhibitors. Similarly, in vivo experiments performed on rats by continuous infusion of FGF2 and a Cx43 HC inhibitor into the 3V, demonstrated that FGF2-induced ß-tanycyte proliferation is sensitive to Cx43 HC blockade. Thus, FGF2 induced Cx43 HC opening, triggered purinergic signaling, and increased ß-tanycytes proliferation, highlighting some of the molecular mechanisms involved in the cell division response of tanycyte. This article has an Editorial Highlight see https://doi.org/10.1111/jnc.15218.

Long-term effects of stress resilience: Hippocampal neuroinflammation and behavioral approach in male rats.

Resilience to stress is the ability to quickly adapt to adversity. There is evidence that exposure to prolonged stress triggers neuroinflammation what produces individual differences in stress vulnerability. However, the relationship between stress resilience, neuroinflammation, and depressive-like behaviors remains unknown. The aim of this study was to analyze the long-term effects of social defeat stress (SDS) on neuroinflammation in the hippocampus and depressive-like behaviors. Male rats were subjected to the SDS paradigm. Social interaction was analyzed 1 and 2 weeks after ending the SDS to determine which animals were susceptible or resilient to stress. Neuroinflammation markers glial fibrillary acidic protein, ionized calcium-binding adaptor molecule 1, and elevated membrane permeability in astrocytes and microglia, as well as depressive-like behaviors in the sucrose preference test and forced swim test were evaluated in all rats. One week after SDS, resilient rats increased their sucrose preference, and time spent in the floating behavior decreased in the forced swim test compared to susceptible rats. Surprisingly, resilient rats became susceptible to stress, and presented neuroinflammation 2 weeks after SDS. These findings suggest that SDS-induced hippocampal neuroinflammation persists in post-stress stages, regardless of whether rats were initially resilient or not. Our study opens a new approach to understanding the neurobiology of stress resilience.

Stretch-Induced Activation of Pannexin 1 Channels Can Be Prevented by PKA-Dependent Phosphorylation.

Pannexin 1 channels located in the cell membrane are permeable to ions, metabolites, and signaling molecules. While the activity of these channels is known to be modulated by phosphorylation on T198, T308, and S206, the possible involvement of other putative phosphorylation sites remains unknown. Here, we describe that the activity of Panx1 channels induced by mechanical stretch is reduced by adenosine via a PKA-dependent pathway. The mechanical stretch-induced activity-measured by changes in DAPI uptake-of Panx1 channels expressed in HeLa cell transfectants was inhibited by adenosine or cAMP analogs that permeate the cell membrane. Moreover, inhibition of PKA but not PKC, p38 MAPK, Akt, or PKG prevented the effects of cAMP analogs, suggesting the involvement of Panx1 phosphorylation by PKA. Accordingly, alanine substitution of T302 or S328, two putative PKA phosphorylation sites, prevented the inhibitory effect of cAMP analogs. Moreover, phosphomimetic mutation of either T302 or S328 to aspartate prevented the mechanical stretch-induced activation of Panx1 channels. A molecular dynamics simulation revealed that T302 and S328 are located in the water-lipid interphase near the lateral tunnel of the intracellular region, suggesting that their phosphorylation could promote conformational changes in lateral tunnels. Thus, Panx1 phosphorylation via PKA could be modulated by G protein-coupled receptors associated with the Gs subunit.

Angiotensin II-Induced Mesangial Cell Damaged Is Preceded by Cell Membrane Permeabilization Due to Upregulation of Non-Selective Channels.

Connexin43 (Cx43), pannexin1 (Panx1) and P2X7 receptor (P2X7R) are expressed in kidneys and are known to constitute a feedforward mechanism leading to inflammation in other tissues. However, the possible functional relationship between these membrane channels and their role in damaged renal cells remain unknown. In the present work, we found that MES-13 cells, from a cell line derived from mesangial cells, stimulated with angiotensin II (AngII) developed oxidative stress (OS, thiobarbituric acid reactive species (TBARS) and generated pro-inflammatory cytokines (ELISA; IL-1ß and TNF-α). The membrane permeability increased progressively several hours before the latter outcome, which was a response prevented by Losartan, indicating the involvement of AT1 receptors. Western blot analysis showed that the amount of phosphorylated MYPT (a substrate of RhoA/ROCK) and Cx43 increased progressively and in parallel in cells treated with AngII, a response followed by an increase in the amount in Panx1 and P2X7R. Greater membrane permeability was partially explained by opening of Cx43 hemichannels (Cx43 HCs) and Panx1 channels (Panx1 Chs), as well as P2X7Rs activation by extracellular ATP, which was presumably released via Cx HCs and Panx1 Chs. Additionally, inhibition of RhoA/ROCK blocked the progressive increase in membrane permeability, and the remaining response was explained by the other non-selective channels. The rise of activity in the RhoA/ROCK-dependent pathway, as well as in Cx HCs, P2X7R, and to a minor extent in Panx1 Chs led to higher amounts of TBARS and pro-inflammatory cytokines. We propose that AngII-induced mesangial cell damage could be effectively inhibited by concomitantly inhibiting the RhoA/ROCK-dependent pathway and one or more non-selective channel(s) activated through this pathway.

Inhibition of glial hemichannels by boldine treatment reduces neuronal suffering in a murine model of Alzheimer's disease.

The contribution of reactive gliosis to the pathological phenotype of Alzheimer's disease (AD) opened the way for therapeutic strategies targeting glial cells instead of neurons. In such context, connexin hemichannels were proposed recently as potential targets since neuronal suffering is alleviated when connexin expression is genetically suppressed in astrocytes of a murine model of AD. Here, we show that boldine, an alkaloid from the boldo tree, inhibited hemichannel activity in astrocytes and microglia without affecting gap junctional communication in culture and acute hippocampal slices. Long-term oral administration of boldine in AD mice prevented the increase in glial hemichannel activity, astrocytic Ca2+ signal, ATP and glutamate release and alleviated hippocampal neuronal suffering. These findings highlight the important pathological role of hemichannels in AD mice. The neuroprotective effect of boldine treatment might provide the basis for future pharmacological strategies that target glial hemichannels to reduce neuronal damage in neurodegenerative diseases.

Exploring the role of moral injury outcomes in intimate relationship functioning among U.S. combat veterans.

OBJECTIVE: Moral injury entails psychological, social, and possible spiritual issues that might interfere with veterans' functioning in romantic or intimate relationships. To date, research has not examined the contribution of moral injury outcomes in this core functional domain in many veterans' lives. METHOD: In total, 65 combat veterans who were engaging in a peer-led intervention for moral injury in a Veteran Service Organization completed the Expressions of Moral Injury Scale, posttraumatic stress disorder (PTSD) checklist for DSM-5, and the romantic relationship subscale of the Inventory of Psychosocial Functioning Scale. RESULTS: Bivariate analyses revealed that moral injury and PTSD symptoms were each associated with worse relationship functioning among the veterans. When including moral injury and PTSD symptoms as predictors in a multivariate analysis, only moral injury was uniquely linked with poorer relationship functioning. CONCLUSIONS: Overall, these findings suggest that moral injury could play a pernicious role in many veterans' issues in relationship problems with their spouses or partners. Future research needs to examine the potential utility of addressing moral injury among veterans who are struggling to meet demands for intimacy and connection in their intimate or romantic relationships. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Chaplain Training in Evidence-Based Practices to Promote Mental Health and Improve Care for Suicidality in Veterans and Service Members.

OBJECTIVE: Chaplains are key care providers in a comprehensive approach to suicide prevention, which is a priority area for the U.S. Department of Veterans Affairs (VA) and the Department of Defense (DoD). In a cohort of 87 VA and military chaplains who completed the Mental Health Integration for Chaplain Services (MHICS) training-an intensive, specialty education in evidence-based psychosocial and collaborative approaches to mental health care-we assessed chaplains' self-perceptions, intervention behaviors, and use of evidence-based practices, including Acceptance and Commitment Therapy (ACT), Problem-Solving Therapy (PST), and Motivational Interviewing (MI), in providing care for suicidality. METHOD: Chaplains responded to a battery of items Pre- and Post-training and provided deidentified case examples describing their use of evidence-based practices in spiritual care for service members and veterans (SM/V) on various levels of a suicide prevention continuum. RESULTS: Post-training, chaplains reported increased abilities to provide care and mobilize collaborative resources. Over the course of MHICS, 87% of chaplains used one or more evidence-based practices with a SM/V at risk for suicide or acutely suicidal. Fifty-six percent of chaplains reported intervening with an acutely suicidal SM/V by using principles from ACT, 36% PST, and 48% MI. With persons at risk for suicide, 81% used principles from ACT, 66% PST, and 71% MI. Cases exemplified diverse evidence-based practice applications. CONCLUSIONS: Findings indicate chaplains trained in evidence-based practices report effective application in caring for SM/V who are suicidal, thus offering a valuable resource to meet needs in a priority area for VA and DoD.HIGHLIGHTSChaplains provide essential care for SM/V who are at risk for suicide or acutely suicidalTraining helps chaplains mobilize interdisciplinary and community resources in suicide careEvidence-based practices can effectively integrate within the scope of chaplaincy practice for suicide care.

Examining the outcomes and acceptability of a peer-led spiritual intervention for moral injury in a veteran service organization.

The purpose of this proof-of-concept study was to examine the outcomes and acceptability of a spiritual intervention for moral injury led by veteran peers in a Veteran Service Organization (VSO), called "Heroes to Heroes." From baseline to 1-year follow-up, 101 veterans who participated in the intervention completed the evaluation surveys at four time points assessing psychological outcomes (moral injury, posttraumatic stress disorder [PTSD] symptoms, and life satisfaction), spiritual outcomes (spiritual struggles and spiritual transcendence), and their perceived helpfulness of the program. In addition, we conducted four focus groups with six to eight alumni to more fully understand veterans' views and experiences of the program. Focusing on the longitudinal surveys, latent growth modeling analyses revealed veterans generally improved across the psychological and spiritual outcomes in the study. Specifically, veterans reported steady decreases in moral injury outcomes, PTSD symptoms, and spiritual struggles along with increased life satisfaction and spiritual transcendence over the 1-year period. An inductive content analysis of veterans' responses to open-ended items in the surveys and focus group interviews revealed four possible mechanisms or facilitators of these outcomes: (a) social connectivity and belonging (e.g., shared vulnerability and camaraderie); (b) behavioral engagement in core aspects of their spirituality (e.g., sacred practices and visiting sacred places); (c) spiritual transformation and growth (e.g., closeness with God and divine forgiveness); and (d) appreciation for diversity (e.g., religious and military). Overall, these findings affirm the potential effectiveness and acceptability of the VSO's peer-led spiritual intervention for promoting the holistic healing among veterans who are contending with emotional and spiritual wounds of war. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Collaborative spiritual care for moral injury in the veterans Affairs Healthcare System (VA): Results from a national survey of VA chaplains.

The psychospiritual nature of moral injury invites consideration regarding how chaplains understand the construct and provide care. To identify how chaplains in the VA Healthcare System conceptualize moral injury, we conducted an anonymous online survey (N = 361; 45% response rate). Chaplains responded to a battery of items and provided free-text definitions of moral injury that generally aligned with key elements in the existing literature, though with different emphases. Over 90% of chaplain respondents indicated that they encounter moral injury in their chaplaincy care, and a similar proportion agreed that chaplains and mental health professionals should collaborate in providing care for moral injury. Over one-third of chaplain respondents reported offering or planning to offer a moral injury group. Separately, nearly one-quarter indicated present or planned collaboration with mental health to provide groups that in some manner address moral injury. Previous training in evidence-based and collaborative care approaches appears to contribute to the likelihood of providing integrated psychosocial-spiritual care. Results and future directions are discussed, including a description of moral injury that may be helpful to understand present areas of emphasis in VA chaplains' care for moral injury.

Excessive release of inorganic polyphosphate by ALS/FTD astrocytes causes non-cell-autonomous toxicity to motoneurons.

Non-cell-autonomous mechanisms contribute to neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), in which astrocytes release unidentified factors that are toxic to motoneurons (MNs). We report here that mouse and patient iPSC-derived astrocytes with diverse ALS/FTD-linked mutations (SOD1, TARDBP, and C9ORF72) display elevated levels of intracellular inorganic polyphosphate (polyP), a ubiquitous, negatively charged biopolymer. PolyP levels are also increased in astrocyte-conditioned media (ACM) from ALS/FTD astrocytes. ACM-mediated MN death is prevented by degrading or neutralizing polyP in ALS/FTD astrocytes or ACM. Studies further reveal that postmortem familial and sporadic ALS spinal cord sections display enriched polyP staining signals and that ALS cerebrospinal fluid (CSF) exhibits increased polyP concentrations. Our in vitro results establish excessive astrocyte-derived polyP as a critical factor in non-cell-autonomous MN degeneration and a potential therapeutic target for ALS/FTD. The CSF data indicate that polyP might serve as a new biomarker for ALS/FTD.

Active acetylcholine receptors prevent the atrophy of skeletal muscles and favor reinnervation.

Denervation of skeletal muscles induces severe muscle atrophy, which is preceded by cellular alterations such as increased plasma membrane permeability, reduced resting membrane potential and accelerated protein catabolism. The factors that induce these changes remain unknown. Conversely, functional recovery following denervation depends on successful reinnervation. Here, we show that activation of nicotinic acetylcholine receptors (nAChRs) by quantal release of acetylcholine (ACh) from motoneurons is sufficient to prevent changes induced by denervation. Using in vitro assays, ACh and non-hydrolysable ACh analogs repressed the expression of connexin43 and connexin45 hemichannels, which promote muscle atrophy. In co-culture studies, connexin43/45 hemichannel knockout or knockdown increased innervation of muscle fibers by dorsal root ganglion neurons. Our results show that ACh released by motoneurons exerts a hitherto unknown function independent of myofiber contraction. nAChRs and connexin hemichannels are potential molecular targets for therapeutic intervention in a variety of pathological conditions with reduced synaptic neuromuscular transmission.

Predictors of dropout from a multidisciplinary heart failure program: a nested case study.

BACKGROUND: Chronic heart failure is a growing public health issue that is reaching epidemic proportions. In the last few years, multidisciplinary management programs have been developed to improve its management. Yet, some patients take advantage of these programs, whereas others do not. METHODS: Several demographic, medical, and social variables were evaluated as contributors to dropout after enrollment into a multidisciplinary heart failure program using a nested case-control design. A total of 14 patients and 42 controls were interviewed using a standardized questionnaire. Possible associations were explored by means of chi Mantel-Haenszel test and a binary logistic regression model. RESULTS: The only significant factor associated with dropout was social isolation. Patients who lived alone, without family support, had a significantly greater dropout risk (odds ratio, 12.5; 95% confidence interval, 1.35-11.6). CONCLUSIONS: For patients who live alone, an individualized approach may be better than a multidisciplinary management program, but this hypothesis should be investigated in future studies.

Pannexin-1 Channels Are Essential for Mast Cell Degranulation Triggered During Type I Hypersensitivity Reactions.

Mast cells (MCs) release pro-inflammatory mediators through a process called degranulation response. The latter may be induced by several conditions, including antigen recognition through immunoglobulin E (IgE) or "cross-linking," classically associated with Type I hypersensitivity reactions. Early in this reaction, Ca2+ influx and subsequent increase of intracellular free Ca2+ concentration are essential for MC degranulation. Several membrane channels that mediate Ca2+ influx have been proposed, but their role remains elusive. Here, we evaluated the possible contribution of pannexin-1 channels (Panx1 Chs), well-known as ATP-releasing channels, in the increase of intracellular Ca2+ triggered during cross-linking reaction of MCs. The contribution of Panx1 Chs in the degranulation response was evaluated in MCs from wild type (WT) and Panx1 knock out (Panx1-/-) mice after anti-ovalbumin (OVA) IgE sensitization. Notably, the degranulation response (toluidine blue and histamine release) was absent in Panx1-/- MCs. Moreover, WT MCs showed a rapid and transient increase in Ca2+ signal followed by a sustained increase after antigen stimulation. However, the sustained increase in Ca2+ signal triggered by OVA was absent in Panx1-/- MCs. Furthermore, OVA stimulation increased the membrane permeability assessed by dye uptake, a prevented response by Panx1 Ch but not by connexin hemichannel blockers and without effect on Panx1-/- MCs. Interestingly, the increase in membrane permeability of WT MCs was also prevented by suramin, a P2 purinergic inhibitor, suggesting that Panx1 Chs act as ATP-releasing channels impermeable to Ca2+. Accordingly, stimulation with exogenous ATP restored the degranulation response and sustained increase in Ca2+ signal of OVA stimulated Panx1-/- MCs. Moreover, opening of Panx1 Chs in Panx1 transfected HeLa cells increased dye uptake and ATP release but did not promote Ca2+ influx, confirming that Panx1 Chs permeable to ATP are not permeable to Ca2+. These data strongly suggest that during antigen recognition, Panx1 Chs contribute to the sustained Ca2+ signal increase via release of ATP that activates P2 receptors, playing a critical role in the sequential events that leads to degranulation response during Type I hypersensitivity reactions.

Cardiovascular risk profile and morbidity in subjects affected by type 2 diabetes mellitus with and without diabetic foot.

Diabetic foot syndrome (DFS) is the most frequent cause of hospitalization of diabetic patients and one of the most economically demanding complications of diabetes. People with diabetes have been shown to have higher mortality than people without diabetes. On this basis, the aim of our study was to evaluate the possible role of diabetic foot as a cardiovascular risk marker in patients with type 2 diabetes mellitus. We enrolled 102 consecutive patients with type 2 diabetes mellitus with diabetic foot and 123 patients with type 2 diabetes mellitus without limb lesions to compare the prevalence of main cardiovascular risk factors, subclinical cardiovascular disease, previous cardiovascular morbidity, and incidence of new vascular events on a 5-year follow-up. Diabetic patients with diabetic foot were more likely to have a higher prevalence of cardiovascular risk factors such as hypercholesterolemia, hypertriglyceridemia, hyperuricemia, and microalbuminuria or proteinuria, a higher prevalence of a previous cardiovascular morbidity (coronary artery disease, transient ischemic attack/ischemic stroke, diabetic retinopathy), and a higher prevalence of subclinical cardiovascular disease. Furthermore, diabetic patients with foot ulceration showed, on a 5-year follow-up, a higher incidence of new-onset vascular events (coronary artery disease, transient ischemic attack/ischemic stroke, diabetic retinopathy). At multivariate analysis, duration of diabetes, age, hemoglobin A1c, and DFS maintained a significant association with cardiovascular morbidity; but DFS presence showed the highest hazard ratio.

Diabetic and non-diabetic subjects with ischemic stroke: differences, subtype distribution and outcome.

BACKGROUND AND AIM: Diabetes mellitus increases the risk of stroke, and pathophysiological changes of diabetic cerebral vessels may differ in comparison with non-diabetic ones; nonetheless, the clinical and prognostic profile of stroke in diabetic patients is not yet fully understood. On this basis, the aim of our study was to evaluate cerebrovascular risk factor prevalence in diabetic stroke patients in comparison with non-diabetics, to analyze whether diabetics have a different prevalence of stroke subtypes as classified by the TOAST classification, and determine whether diabetics and non-diabetics have a different prognosis. METHODS AND RESULTS: We enrolled 102 diabetics and 204 non-diabetic subjects with acute ischemic stroke, matched by sex and age (+/-3 years). We used as outcome indicators the Scandinavian Stroke Scale (SSS) score at admission and the modified Rankin disability scale at discharge and at a 6-month follow-up. We classified ischemic stroke according to the TOAST classification. Diabetes was associated with lacunar ischemic stroke subtype, with a record of hypertension, and with a better SSS score at admission. The association of diabetes with lacunar stroke remained significant even after adjustment for hypertension or for large artery atherosclerotic and cardioembolic stroke subtypes. CONCLUSION: Our study shows some significant differences in acute ischemic stroke among diabetics in comparison with non-diabetics (higher frequency of hypertension, higher prevalence of lacunar stroke subtype, lower neurological deficit at admission in diabetics).